Benzimidazole compounds containing 1,2,4-triazole ring, and compositions and methods of use containing the same

ABSTRACT

Benzimidazole compounds represented by the formula set out below and analogs thereof, wherein Y represents a single bond or sulfur atom; Z represents oxygen atom, sulfur atom, or N—R 4 ; R 1  and R 2  independently represent hydrogen, a halogen atom, alkyl group or other; R 3  and R 4  independently represent hydrogen, alkyl group, acyl group or other; n and m independently represent an integer of 1, 2, or 3; and L represents a linking group such as C 2-12  alkylene group or an alkylene group containing one or more phenylene groups or ether groups. The compounds are useful as an active ingredient of a medicament such as a preventive and therapeutic medicament for hyperlipemia or arterial sclerosis.

TECHNICAL FIELD

This application is a divisional of application No. 09/000,351, filed onJan. 16, 1998, now U.S. Pat. No. 5,998,456, the entire contents of whichare hereby incorporated by reference. This application claims thebenefit under 35 U.S.C. § 371 of prior PCT International Application No.PCT/JP/01949 which has an International filing date of Jul. 12, 1997which designated the United States of America, the entire contents ofwhich are hereby incorporated by reference.

The present invention relates to benzimidazole compounds. Moreprecisely, the present invention relates to novel bis-type benzimidazolecompounds which are useful as an active ingredient of a medicament fortherapeutic and preventive treatment of hyperlipemia, arterial sclerosisand the like, or useful as an additive of a silver halide photosensitivematerial, a liquid crystal material and the like.

BACKGROUND ART

In recent years, patients with so-called adult diseases such as arterialsclerosis, hypertension, and diabetes mellitus have been continuouslyincreasing with prolongation of life expectancy. In particular, patientswith hyperlipemia and arterial sclerosis derived therefrom have beenremarkably increasing due to excessive intake of high calorie and highcholesterol food, which have become a serious social problem.Medicaments currently used for drug therapy of hyperlipemia and arterialsclerosis are those symptomatically lower cholesterol in blood, andtherefore, they cannot be expected to have potency in retractingarterial sclerosis lesions, per se. Arterial sclerosis is characterizedby lesions of intimal hyperplasia and lipid accumulation in bloodvessels, and it has been elucidated from recent biochemical findingsthat foaming of macrophages plays a main role in the formation ofarterial sclerosis lesions. Accordingly, suppression of the foaming ofmacrophages may possibly prevent arterial sclerosis by inhibitingformation of arterial sclerosis lesions, or achieve radicular treatmentof arterial sclerosis by retraction of arterial sclerosis lesions.However, no medicament having such activity has been known.

Therefore, an object of the present invention is to provide a compoundhaving activity of suppressing the foaming of macrophages, and is usefulas an active ingredient of a medicament for preventive and/ortherapeutic treatment of arterial sclerosis. Another object of thepresent invention is to provide a compound having the aforementionedactivity, and is useful as an active ingredient of medicament forpreventive and/or therapeutic treatment of hyperlipemia.

DISCLOSURE OF THE INVENTION

The inventors of the present invention conducted various research toachieve the foregoing objects, and as a result, they found that novelbenzimidazole compounds represented by the formulas set out below haveactivity of suppressing the foaming of macrophages, and are useful asactive ingredients of preventive and therapeutic medicament of arterialsclerosis and preventive and therapeutic medicament of hyperlipemia. Thepresent invention was achieved on the basis of this finding.

According to the first aspect of the present invention, there areprovided benzimidazole compounds represented by the following formula(IA):

wherein, Y represents a single bond or sulfur atom; Z represents oxygenatom, sulfur atom or N—R⁴; R¹ and R² independently represent hydrogenatom, a halogen atom, an alkyl group, a haloalkyl group, an aryl group,an alkoxy group, an aryloxy group, an alkoxycarbonyl group, a carbamoylgroup, a sulfamoyl group, an acylamino group, a sulfonylamino group,cyano group, hydroxyl group, or nitro group; R³ and R⁴ independentlyrepresent hydrogen atom, an alkyl group, an acyl group, a sulfonylgroup, an alkoxycarbonyl group, a sulfamoyl group, or a carbamoyl group;n and m each independently represent an integer of 1, 2 or 3, and wheren or m represents 2 or 3, two or three R¹ or R² which may be the same ordifferent substitute on the benzene ring, respectively; and L representsa linking group selected from a group consisting of a C₂₋₁₂ alkylenegroup, and an alkylene group containing one or more phenylene groups orether groups and having 4-12 atoms that constitute a full length of alinking chain; provided that R¹ and R² do not represent the samesubstituents when Y is sulfur atom, Z is N—R⁴, n=m, and R³ and R⁴represent the same substituents.

According to the second aspect of the present invention, there areprovided benzimidazole compounds represented by the following formula(IB):

wherein, Y represents a single bond or sulfur atom; R⁵ representshydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, anaryl group, an alkoxy group, an aryloxy group, an alkoxycarbonyl group,a carbamoyl group, a sulfamoyl group, an acylamino group, asulfonylamino group, cyano group, hydroxyl group, or nitro group; R⁶represents hydrogen atom, an alkyl group, an acyl group, a sulfonylgroup, an alkoxycarbonyl group, a sulfamoyl group, or a carbamoyl group;n represents an integer of 1, 2 or 3, and when n represents 2 or 3, twoor three R⁵ which may be the same or different substitute on the benzenering, respectively; L represents a linking group selected from a groupconsisting of a C₂₋₁₂ alkylene group, and an alkylene group containingone or more phenylene groups or ether groups and having 4-12 atoms thatconstitute a full length of a linking chain; and Q represents asubstituted or unsubstituted 5- or 6-membered heterocyclic group, or asubstituted or unsubstituted condensed heterocyclic group containing8-10 ring-membered atoms.

The present invention further provides methods for preparing thecompounds represented by the above formula (IA) or (IB), medicamentscomprising the compounds represented by the above formula (IA) or (IB),and methods for manufacturing the medicaments comprising the compoundsrepresented by the above formula (IA) or (IB). As a preferred embodimentof the medicament of the present invention, there is provided apharmaceutical composition which comprises the aforementioned compoundas an active ingredient together with a pharmaceutical additive. Thepharmaceutical compositions of the present invention are useful as, forexample, a preventive and/or therapeutic medicament for hyperlipemia, apreventive and/or therapeutic medicament for arterial sclerosis, anagent for suppressing foaming of macrophages, an agent for retractingarterial sclerosis lesions, an agent for inhibiting the formation ofarterial sclerosis lesions, a cholesterol-lowering agent and the like.Use of the compounds represented by the above formula (IA) or (IB) forthe manufacture of the aforementioned pharmaceutical composition is alsoprovided as an aspect of the present invention.

According to further aspects of the present invention, there areprovided a method for preventive and/or therapeutic treatment of adisease selected from a group consisting of hyperlipemia and arterialsclerosis, which comprises the step of administering a preventively ortherapeutically effective amount of the compound represented by theabove formula (IA) or (IB) to a patient, and a method for preventiveand/or therapeutic treatment of a disease caused by the foaming ofmacrophages, which comprises the step of administering a preventively ortherapeutically effective amount of the compound represented by theabove formula (IA) or (IB) to a patient.

BEST MODE FOR CARRYING OUT THE INVENTION

In the above formula (IA), Y represents a single bond or sulfur atom.When Y represents a single bond, the carbon atom between the twonitrogen atoms of the imidazole ring to which R³ binds (2-positioncarbon atom of the benzimidazole ring) directly binds to the linkinggroup L. Among them, Y is preferably sulfur atom. Z represents oxygenatom, sulfur atom, or N—R⁴, thereby a condensed heterocyclic ringcontaining Z represents benzoxazole, benzothiazole, or benzimidazolering.

R¹ and R² independently represent a hydrogen atom, a halogen atom, analkyl group, an aryl group, an alkoxy group, an aryloxy group, analkoxycarbonyl group, carbamoyl group, sulfamoyl group, an acylaminogroup, a sulfonylamino group, cyano group, hydroxyl group, or nitrogroup, and n and m independently represent an integer of 1,2, or 3. Itis preferred that R¹ and R² independently represent hydrogen atom, ahalogen atom, an alkyl group, an alkoxy group, an acylamino group,sulfonylamino group, or an alkoxycarbonyl group, and it is particularlypreferred that they independently represent hydrogen atom, chlorineatom, a C₁₋₄ alkyl group, or a C₁₋₄ alkoxy group. When Z is N—R⁴, it ispreferred that either of R¹ and R² is hydrogen atom.

When n represents 1, the definition means that one R¹ substitutes at anarbitrary position of the benzene ring. When n represents 2 or 3, thedefinition means that two or three R¹ groups substitute at arbitrarypositions of the benzene ring. When n represents 2 or 3, two or three R¹groups may be the same or different. Similarly, when m represents 1, thedefinition means that one R² substitutes at an arbitrary position of thebenzene ring, and when n represents 2 or 3, the definition means thattwo or three R² groups substitute at arbitrary positions of the benzenering. When n represents 2 or 3, two or three R² groups may be the sameor different. It is preferred that R¹ and R² substitute at 5- and/or6-positions of the condensed heterocyclic ring containing thebenzimidazole ring and the heterocyclic ring containing Z, respectively.

Specific examples of substituents represented by R¹ and R² will beexplained below. As the halogen atom, fluorine atom, chlorine atom,bromine atom, or iodine atom may be used, and preferably fluorine atom,chlorine atom, or bromine atom may be used. Chlorine atom may mostpreferably be used. As the alkyl group, a straight-chain,branched-chain, or cyclic C₁₋₁₈ (containing 1-18 carbon atoms) alkylgroup may be used. For example, methyl group, ethyl group, n-propylgroup, isopropyl group, n-butyl group, sec-butyl group, tert-butylgroup, cyclopropyl group, cyclohexyl group, n-octyl group, n-dodecylgroup and n-octadecyl group may be used. Preferably, a straight-chain,branched-chain, or cyclic-C₁₋₈ alkyl group, and more preferably, astraight-chain or branched-chainC₁₋₄ alkyl group may be used. Methylgroup may most preferably be used.

Examples of the haloalkyl group include those having one or more halogenatoms, which may be the same or different, substituted on theaforementioned straight-chain, branched-chain, or cyclic C₁₋₁₈ alkylgroup, preferably the straight-chain, branched, or cyclic C₁₋₈ alkylgroup, more preferably the straight-chain or branched C₁₋₄ alkyl group.As the halogen atom, for example, fluorine atom or chlorine atom, morepreferably fluorine atom may be used. For example, monochloromethylgroup, trifluoromethyl group, 2,2,2-trifluoroethyl group,pentafluoroethyl group or the like may be used, and most preferably,trifluoromethyl group may be used.

Examples of the aryl group include a substituted or unsubstituted C₆₋₁₄aryl group such as a substituted or unsubstituted phenyl group or asubstituted or unsubstituted naphthyl group. Preferably, a substitutedor unsubstituted phenyl group, and more preferably, unsubstituted phenylgroup may be used. Examples of a substituent of the aryl group includethe alkyl group, the haloalkyl group, and the halogen mentioned above,hydroxyl group, alkoxy groups mentioned below and the like. As thearyloxy group, a C₆₋₁₄ aryloxy group formed by substituting one hydrogenatom on a ring of the above aryl groups with oxygen atom may be used.For example, phenoxy group, 1-naphthyloxy group, 2-naphthyloxy group orthe like may be used.

As the alkoxy group, straight-chain, branched-chain, or cyclic C₁₋₁₈alkoxy group may be used. For example, methoxy group, ethoxy group,n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group,tert-butoxy group, cyclohexyloxy group, n-octyloxy group, n-dodecyloxygroup and n-octadecyloxy group may be used. Preferably, astraight-chain, branched-chain, or cyclic C₁₋₈ alkoxy group, and morepreferably, a straight-chain or branched-chainC₁₋₄ alkoxy group, andmost preferably, methoxy group or ethoxy group may be used. Examples ofthe alkoxycarbonyl group include carbonyl groups substituted with theaforementioned straight-chain, branched-chain, or cyclic C₁₋₁₈ alkoxygroup, preferably a straight-chain, branched-chain, or cyclic-C₁₋₈alkoxy group, and more preferably a straight-chain or branched-chainC₁₋₄alkoxy group. For example, methoxycarbonyl group, ethoxycarbonyl group,n-butoxycarbonyl, tert-butoxycarbonyl group, n-octyloxycarbonyl group,n-dodecyloxycarbonyl group, n-octadecyloxycarbonyl group or the like,and preferably methoxycarbonyl group or ethoxycarbonyl group may beused.

As the carbamoyl group, a substituted or unsubstituted carbamoyl groupmay be used, and as the substituted carbamoyl group, a mono- ordisubstituted carbamoyl group may be used. As one or two functionalgroups substituting on the carbamoyl group, for example, theaforementioned C₁₋₁₈ alkyl groups or the aforementioned C₆₋₁₄ arylgroups may be used. It is desirable that the total number of carbonatoms contained in the one or two functional groups may be 18 or less,preferably 12 or less, and more preferably 6 or less. Examples of thesubstituted carbamoyl group include methylcarbamoyl group,diethylcarbamoyl group, n-octylcarbamoyl group, n-hexadecylcarbamoylgroup and phenylcarbamoyl group, preferably methylcarbamoyl group or thelike.

As the sulfamoyl group, a substituted or unsubstituted sulfamoyl groupmay be used, and as the substituted sulfamoyl group, a mono- ordisubstituted sulfamoyl group may be used. As one or two functionalgroups substituting on the sulfamoyl group, for example, theaforementioned C₁₋₁₈ alkyl groups or the aforementioned C₆₋₁₄ arylgroups may be used. It is desirable that the total number of carbonatoms contained in the one or two functional groups may be 18 or less,preferably 12 or less, and more preferably 6 or less. As the substitutedsulfamoyl group, for example, methylsulfamoyl group, diethylsulfamoylgroup, n-octylsulfamoyl group, n-hexadecylsulfamoyl group,phenylsulfamoyl group or the like, and preferably methylsulfamoyl groupmay be used.

As an acyl group constituting the acylamino group, an alkylcarbonylgroup comprising carbonyl group substituted with the aforementionedC₁₋₁₈ alkyl group, a haloalkylcarbonyl group having the aforementionedhalo-C₁₋₁₈ alkyl group, or an arylcarbonyl group having theaforementioned C₆₋₁₄ aryl group may be used. It is desirable that thenumber of carbon atoms of the alkyl group, haloalkyl group, or arylgroup which substitutes on the carbonyl group may preferably be 12 orless, and more preferably 6 or less. As the acylamino group, forexample, acetylamino group, trifluoroacetylamino group, propionylaminogroup, n-butanoylamino group, n-octanoylamino group, n-hexadecanoylaminogroup, benzoylamino group or the like, preferably, acetylamino group orpropionylamino group, and most preferably, propionylamino group may beused.

As sulfonyl group constituting the sulfonylamino group, an alkylsulfonylgroup comprising sulfonyl group substituted with the aforementionedC₁₋₁₈ alkyl group, a haloalkylsulfonyl group having the aforementionedhalo-C₁₋₁₈ alkyl group, an arylsulfonyl group having the aforementionedC₆₋₁₄ aryl groups may be used. It is desirable that the number of carbonatoms of the alkyl group, haloalkyl group, or aryl group whichsubstitute on the sulfonyl group may preferably be 12 or less, and morepreferably 6 or less. As the sulfonylamino group, for example,methanesulfonylamino group, trifluoromethanesulfonylamino group,ethanesulfonylamino group, n-butane-sulfonylamino group,n-octanesulfonylamino group, n-hexadecanesulfonylamino group,benzenesulfonylamino group, p-toluenesulfonylamino group or the like,and preferably, methanesulfonylamino group may be used.

R³ and R⁴ independently represent hydrogen atom, an alkyl group, an acylgroup, a sulfonyl group, an alkoxycarbonyl group, a sulfamoyl group, ora carbamoyl group. As the alkyl group represented by R³ and R⁴, theaforementioned C₁₋₁₈ alkyl group may be used. Among them, preferably astraight-chain or branched-chain group, more preferably a straight-chainor branched-chain C₁₋₈ alkyl group, further preferably a straight-chainor branched-chain C₁₋₄ alkyl group, and most preferably methyl may beused. As the acyl group represented by R³ and R⁴, an alkylcarbonyl groupcomprising carbonyl group substituted with the aforementioned C₁₋₁₈alkyl group, a haloalkylcarbonyl group having the aforementionedhalo-C₁₋₁₈ alkyl group, an arylcarbonyl group having the aforementionedC₆₋₁₄ aryl groups may be used.

As the sulfonyl group represented by R³ and R⁴, an alkylsulfonyl groupcomprising sulfonyl group substituted with the aforementioned C₁₋₁₈alkyl group, haloalkylsulfonyl group having the aforementionedhalo-C₁₋₁₈ alkyl group, an arylsulfonyl group having the aforementionedC₆₋₁₄ aryl group may be used. As the alkoxycarbonyl group, carbonylgroup substituted with the aforementioned C₁₋₁₈ alkoxy group, preferablya C₁₋₈ alkoxy group, more preferably a straight-chain or branched-chainC₁₋₄ alkoxy group may be used. As the carbamoyl group and the sulfamoylgroup, the substituted or unsubstituted carbamoyl groups and sulfamoylgroups explained above may be used. It is preferred that R³ and R⁴independently represent hydrogen atom, a straight-chain orbranched-chain C₁₋₅ alkyl group, a straight-chain or branched-chain C₁₋₄alkylcarbonyl group or the like. Most preferably, R³ and R⁴ are hydrogenatoms.

In the above formula (IA), L represents a linking group, and thislinking group is selected from L represents a linking group selectedfrom a group consisting of a C₂₋₁₂ alkylene group, and an alkylene groupcontaining one or more phenylene groups or ether groups and having 4-12atoms that constitute a full length of a linking chain. These alkylenegroups may be substituted with other substituents, and the alkylene maybe a straight-chain or branched-chain. As the C₂₋₁₂ alkylene group, forexample, ethylene group, 1,4-butylene group, 1,5-pentylene group,1,6-hexylene group, 1,10-decylene group or the like may be used.Preferably, a straight-chain or branched-chain C₄₋₁₂ alkylene group,more preferably a straight-chain or branched-chain C₄₋₁₁ alkylene group,further preferably a linear C₄₋₈ alkylene group, and most preferably aC₅₋₆ alkylene group may be used.

When L contains one or more phenylene groups or ether groups, number ofcarbon atoms and oxygen atoms constituting a chain moiety of the linkinggroup (these atoms are referred to as “atoms constituting a full lengthof a linking chain”) are from 4 to 12 (for phenylene group, the numbersof the atoms is considered as 4). The phenylene group may have one ormore substituents which may be the same or different and selected from,for example, those explained above as to R¹, e.g., an alkyl group, ahaloalkyl group, a halogen atom, an alkoxy group, hydroxyl group and thelike.

Examples of the linking group containing phenylene group include, forexample, alkylene-phenylene-alkylene groups such as 1,4-xylylene group,1,3-xylylene group, 1,2-xylylene group, and 2-ethylene-4-phenylmethylgroup, and examples of the linking group containing ether group include,for example, ethylyleneoxyethyl group and ethyleneoxyethoxyethyl group.L is preferably a C₄₋₈ alkylene group or ethyleneoxyethyl group, andmost preferably a C₅₋₆ alkylene group. In the compounds of the presentinvention represented by the formula (IA), the two partial moiety thatare bound by means of the linking group L (the right partial structureand the left partial structure bridged with L in the formula A)) are notidentical to each other. In addition, when Y is sulfur atom, Z is N—R⁴,n=m, and R¹ and R⁴ are the same substituents, R¹ and R² do not representidentical substituents. More preferably, where Y is sulfur atom, Z isN—R⁴, and n=m, R³ and R⁴ do not represent identical substituents when R¹and R² are the same substituents.

As preferred compounds represented by the formula (IA), there areprovided:

(a) the aforementioned compounds wherein Y represents a single bond orsulfur atom; Z represents oxygen atom, sulfur atom or N—R⁴; R¹ and R²independently represent hydrogen atom, a halogen atom, an alkyl group, ahaloalkyl group, an aryl group, an alkoxy group, an alkoxycarbonylgroup, a sulfamoyl group, an acylamino group, a sulfonylamino group,cyano group, hydroxyl group, or nitro group; R³ and R⁴ independentlyrepresent hydrogen atom, an alkyl group, or an acyl group; n and mindependently represent 1 or 2; and L represents a linking groupselected from a C₄₋₁₁ alkylene group, or an alkylene group containingone or more ether groups and having 5-8 atoms constituting a full lengthof a linking chain;

(b) the aforementioned compounds wherein Y represents a single bond orsulfur atom; Z represents oxygen atom, sulfur atom or N—R⁴; R¹ and R²independently represent hydrogen atom, a halogen atom, a C₁₋₄ alkylgroup, a halo-C₁₋₄ alkyl group, phenyl group, a C₁₋₄ alkoxy group, aC₁₋₄ alkoxycarbonyl group, a C₁₋₄ alkylsulfamoyl group, a C₁₋₄alkylcarbonylamino group, a C₁₋₄ alkylsulfonylamino group, cyano group,hydroxyl group, or nitro group; R³ and R⁴ independently representhydrogen atom, a C₁₋₄ alkyl group, or an C₁₋₄ alkylcarbonyl group; n andm independently represent 1 or 2; and L represents a linking groupselected from a C₄₋₁₁ alkylene group, or an alkylene group containingone or more ether groups and having 5-8 atoms constituting a full lengthof a linking chain;

(c) the aforementioned compounds wherein Y represents a single bond orsulfur atom; R¹ represents hydrogen atom, a halogen atom, a C₁₋₄ alkylgroup, or nitro group; n represents 1 or 2; R² represents hydrogen atom,a halogen atom, a C₁₋₄ alkyl group, a halo-C₁₋₄ alkyl group, phenylgroup, a C₁₋₄ alkoxy group, a C₁₋₄ alkoxycarbonyl group, a C₁₋₄alkylsulfamoyl group, a C₁₋₄ alkylcarbonylamino group, a C₁₋₄alkylsulfonylamino group, cyano group, or hydroxyl group; m represents 1or 2; R³ represents hydrogen atom, a C₁₋₄ alkyl group or a C₁₋₄alkylcarbonyl group; Z represents oxygen atom, sulfur atom or N—R⁴wherein R⁴ represents hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄alkylcarbonyl group; and L represents a linking group selected from aC₄₋₁₁ alkylene group and an alkylene group containing one or more ethergroups and having 5-8 atoms constituting a full length of a linkingchain;

(d) the aforementioned compounds according to the above (c), wherein R²is hydrogen atom when Y represents a single bond;

(e) the aforementioned compounds according to the above (c) or (d),wherein Y is sulfur atom when L represents an alkylene group containingone or more ether groups and having 5-8 atoms constituting a full lengthof a linking chain;

(f) the aforementioned compounds according to the above (e), wherein R¹represents a halogen atom; n represents 1 or 2; R² represents a halogenatom; and m represents 1 or 2;

(g) the aforementioned compounds according to the above (e), wherein R¹represents a halogen atom; n represents 1 or 2; R² represents a halogenatom; and m represents 2; and

(h) each of the aforementioned compounds, wherein R¹ and R² aresubstituents at 5- and/or 6-position of the respective condensedheterocyclic rings.

Among the compounds of the above formula (IA), examples of the mostpreferred compounds according to the present invention include each ofthe compounds wherein, as to the substituents represented by R¹ and/orR², the halogen atom is chlorine atom, the C₁₋₄ alkyl group is methylgroup, the halo-C₁₋₄ alkyl group is trifluoromethyl group, the C₁₋₄alkoxy group is methoxy group or ethoxy group, the C₁₋₄ alkoxycarbonylgroup is ethoxycarbonyl group, the C₁₋₄ alkylsulfamoyl group ismethylsulfamoyl group, the C₁₋₄ alkylcarbonylamino group isethylcarbonylamino group, and the C₁₋₄ alkylsulfonylamino group ismethylsulfonylamino group; and as to the substituents represented by R³and/or R⁴, the C₁₋₄ alkyl group is methyl group, the C₁₋₄ alkylcarbonylgroup is ethylcarbonyl group, and the alkylene group containing one ormore ether groups and having 5-8 atoms constituting a full length of alinking chain represented by L is ethylyleneoxyethyl group orethyleneoxyethoxyethyl group

Among the compounds of the present invention represented by the formula(IA), Compounds A1 to Compound A39 are shown below as examples ofparticularly preferred compounds. However, the scope of the presentinvention is not limited to these compounds.

In the aforementioned formula (IB) according to the second aspect of thepresent invention, Y represents a single bond or sulfur atom. When Yrepresents a single bond, the carbon atom between the two nitrogen atomsof the imidazole ring to which R⁶ binds (the carbon atom at the2-position of the benzimidazole ring) is directly bound to the linkinggroup L. Y is preferably sulfur atom.

R⁵ represents hydrogen atom, a halogen atom, an alkyl group, a haloalkylgroup, an aryl group, an alkoxy group, an aryloxy group, analkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, an acylaminogroup, a sulfonylamino group, cyano group, hydroxyl group, or nitrogroup, and n represents an integer of 1, 2 or 3. R⁵ preferablyrepresents hydrogen atom, a halogen atom, an alkyl group, an alkoxygroup, an alkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, anacylamino group, a sulfonylamino group, or nitro group. R¹ mostpreferably represents hydrogen atom, chlorine atom, a C₁₋₄ alkyl group,a C₁₋₄ alkoxy group, a C₁₋₄ alkoxycarbonyl group, a substituted orunsubstituted carbamoyl group, a substituted or unsubstituted sulfamoylgroup, an acylamino group, sulfonylamino group, or nitro group.

When n represents 1, the definition means that one R¹ substitutes at anarbitrary position of the benzene ring. When n represents 2 or 3, thedefinition means that two or three R⁵ groups substitute at arbitrarypositions of the benzene ring. When n represents 2 or 3, two or three R⁵groups may be the same or different. It is preferred that one or two R⁵substitute at 5- and/or 6- positions of the benzimidazole ring. As thesubstituent represented by R⁵, i.e., a halogen atom, an alkyl group, ahaloalkyl group, an aryl group, an aryloxy group, an alkoxy group, analkoxycarbonyl group, a carbamoyl group, a sulfamoyl group, an acylgroup constituting an acylamino group, and a sulfonyl group constitutinga sulfonylamino group, those specifically explained above as to R¹ andR² may be used.

R⁶ represents hydrogen atom, an alkyl group, an acyl group, a sulfonylgroup, an alkoxycarbonyl group, a sulfamoyl group, or a carbamoyl group,and as the functional groups, those specifically explained above as toR³ and R⁴ may be used. R⁶ preferably represents hydrogen atom, astraight-chain or branched-chain C₁₋₅ alkyl group, a straight-chain orbranched-chain C₁₋₄ alkylcarbonyl group or the like, and most preferablyrepresents hydrogen atom.

In the above formula (IB), L represents a linking group, and the linkinggroup is selected from a C₂₋₁₂ alkylene group, or an alkylene groupcontaining one or more phenylene groups or ether groups and having 4-12atoms constituting a full length of a linking chain. As these linkinggroup, those specifically explained as L of the compounds of the formula(IA) may be used.

Q represents a 5- or 6-membered heterocyclic group, or a condensedheterocyclic group containing 8-10 ring-membered atoms. Theseheterocyclic groups may be substituted or unsubstituted. Numbers ofhetero atoms contained in the above heterocyclic ring is notparticularly limited so long as the ring contains at least one heteroatom, and the ring may be constituted only by heteroatoms. The sort ofthe hetero atoms is not particularly limited. For example, nitrogenatom, sulfur atom, oxygen atom or the like may be used.

The heterocyclic ring that constitutes the 5- or 6-membered heterocyclicgroup may be either saturated or unsaturated. For example, pyridine(e.g., 2-pyridyl group or 4-pyridyl group), pyrimidine (e.g.,2-pyrimidyl group or 4-pyrimidyl group), pyrazine (e.g., 2-pyrazylgroup), piperidine (e.g., 2-piperidyl group), piperazine (e.g.,2-piperazyl group), morpholine (e.g., 2-morpholino group), quinoline(e.g., 2-quinolyl group, 4-quinolyl group, 8-quinolyl group), pyrrole(e.g., 2-pyrrolyl group), thiophene (e.g., 2-thienyl group), furan(e.g., 2-furyl group), imidazole (e.g., 2- imidazolyl group), triazole(e.g., 1,2,4-triazol-3-yl group), tetrazole (e.g., 1,2,3,4-tetrazol-5-ylgroup), thiazole (e.g., 2-thiazolyl group, 3-isothiazolyl group),thiaziazole (e.g., 2-thiadiazolyl group), oxazole (e.g., 2-oxazolylgroup, 3-isoxazolyl group), oxadiazole (e.g., 2-oxadiazolyl group),purine (e.g., 6-purinyl group, 8-purinyl group),pyrazolo[3,4-d]pyrimidine (e.g., 1H-pyrazolo[3,4-d]pyrimidin-4-yl group)or the like.

As the heterocyclic group containing 8-10 ring-membered atoms, thoseformed by condensation of the aforementioned 5- or 6-memberedheterocyclic group with one benzene ring or the aforementioned 5- or6-membered heterocyclic ring may be used. Where the aforementionedheterocyclic ring or the condensed heterocyclic ring is substituted,examples of the substituent include, for example, a halogen atom, analkyl group, a haloalkyl group, an aryl group, an alkoxy group, anaryloxy group, an alkoxycarbonyl group, a carbamoyl group, a sulfamoylgroup, an acylamino group, and a sulfonylamino group as explained aboveas to R⁵; the aforementioned 5- or 6-membered heterocyclic group; nitrogroup; a substituted or unsubstituted amino group, e.g., amino group, amonoalkylamino group, and a dialkylamino group; hydroxyl group; analkylthio group which comprises thiol group substituted with theaforementioned alkyl group; an arylthio group which comprises thiolgroup substituted with the aforementioned aryl group; mercapto group;cyano group; oxo group; thioxo group; oxide group on a nitrogen atomthat constitutes a heterocyclic ring; and the aforementioned 5- or6-membered heterocyclic group and the like.

However, compounds wherein Q represents a substituted or unsubstituted2-benzimidazolyl group, a substituted or unsubstituted 2-benzoxazolylgroup, a substituted or unsubstituted 2-benzothiazolyl group, and asubstituted or unsubstituted 4,5-diphenyl-2-imidazolyl group areexcluded from the scope of the present invention.

As preferred embodiments of the compounds represented by the formula(IB), there are provided:

(i) the aforementioned compounds, wherein Y represents a single bond orsulfur atom; R⁵ represents hydrogen atom, a halogen atom, an alkylgroup, an alkoxy group, an alkoxycarbonyl group, a carbamoyl group, asulfamoyl group, an acylamino group, a sulfonylamino group, or nitrogroup; R⁶ represent hydrogen atom, an alkyl group, or an acyl group; nrepresents 1 or 2; and L represents a linking group selected from aC₄₋₁₁ alkylene group or an alkylene group containing one or more ethergroups and having 5-8 atoms constituting a full length of a linkingchain;

(j) the aforementioned compounds, wherein Y represents a single bond orsulfur atom; R⁵ represents hydrogen atom, a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a C₁₋₄ alkoxycarbonyl group, a substitutedor unsubstituted carbamoyl group, a substituted or unsubstitutedsulfamoyl group, an acylamino group, a sulfonylamino group, or nitrogroup; R⁶ represents hydrogen atom, a C₁₋₄ alkyl group or a C₁₋₄alkylcarbonyl group; n represents 1 or 2; and L represents a linkinggroup selected from a C₄₋₁₁ alkylene group or an alkylene groupcontaining one or more ether groups and having 5-8 atoms constituting afull length of a linking chain;

(k) the aforementioned compounds, wherein Y represents a single bond orsulfur atom; R⁵ represents hydrogen atom, a halogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group, a C₁₋₄ alkoxycarbonyl group, a C₁₋₄alkylcarbamoyl group, a C₁₋₄ alkylsulfamoyl group, a C₁₋₄alkylcarbonylamino group, a C₁₋₄ alkylsulfonylamino group, or nitrogroup; R⁶ represents hydrogen atom, a C₁₋₄ alkyl group, or a C₁₋₄alkylcarbonyl group; n represents 1 or 2; and L represents a linkinggroup selected from a C₄₋₁₁ alkylene group or an alkylene groupcontaining one or more ether groups and having 5-8 atoms constituting afull length of a linking chain;

(l) the aforementioned compounds according to the above (k), wherein nrepresents 2, and two R⁵ groups substitute at the 5- and 6-positions ofthe benzimidazole ring;

(m) the aforementioned compounds according to the above (k) or (l),wherein R⁵ represents hydrogen atom, a halogen atom, a C₁₋₄ alkyl group,or nitro group, and R⁶ represents hydrogen atom when Y represents asingle bond;

(n) the aforementioned compounds according to the above (k), wherein Yrepresents sulfur atom when L represents an alkylene group containingone or more ether groups and having 5-8 atoms constituting a full lengthof a linking chain;

(o) the aforementioned compounds according to the above (n), wherein R⁵represents hydrogen atom; and

(p) the aforementioned compounds according to the above (o), wherein Qrepresents a 5-membered heterocyclic group.

Among the compounds of the above formula (IB), examples of the mostpreferred compounds according to the present invention include each ofthe compounds wherein, as to the substituents represented by R⁵, thehalogen atom is chlorine atom, the C₁₋₄ alkyl group is methyl group, theC₁₋₄ alkoxy group is methoxy group or ethoxy group, the C₁₋₄alkoxycarbonyl group is ethoxycarbonyl group, the C₁₋₄ alkylsulfamoylgroup is methylsulfamoyl group, the C₁₋₄ alkylcarbonylamino group isethylcarbonylamino group, the C₁₋₄ alkylsulfonylamino group ismethylsulfonylamino group; and as to the substituents represented by R⁶,the C₁₋₄ alkyl group is methyl group, the C₁₋₄ alkylcarbonyl group isethylcarbonyl group; and the alkylene group containing one or more ethergroups and having 5-8 atoms constituting a full length of a linkingchain represented by L is ethylyleneoxyethyl group orethyleneoxyethoxyethyl group.

Among the compounds of the present invention represented by the formula(IB), Compounds B1 to Compound B68 are shown below as examples ofparticularly preferred compounds. However, the scope of the presentinvention is not limited to these compounds. Group Q in the compoundsset out below should be understood as preferred examples of Q.

No. R¹¹ R¹² R² Y m Q  (1) H H H S 5

 (2) H H H S 5

 (3) H H H S 5

 (4) H H H S 5

 (5) H H H S 5

 (6) H H H S 5

 (7) H H H S 5

 (8) H H H S 5

 (9) H H H S 5

(10) H H H S 5

(11) H H H S 5

(12) H H H S 5

(13) H H H S 5

(14) H H H S 5

(15) H H H S 5

(16) H H H S 5

(17) H H H S 5

(18) H H H S 5

(19) H H H S 5

(20) H H H S 5

(21) H H H S 5

(22) H H H S 5

(23) H H H S 5

(24) H H H S 5

(25) H H H S 5

(26) H H H S 5

(27) H H H S 5

(28) H H H S 5

(29) H H H S 4

(30) H H H S 5

(31) H H H S 6

(32) H H H S 8

(33) CH₃ CH₃ H S 5

(34) OCH₃ H H S 5

(35) CH₃ H H S 5

(36) COOC₂H₅ H H S 5

(37) NHCOC₂H₅ H H S 5

(38) NHSO₂CH₃ H H S 5

(39) CON(CH₃)₂ H H S 5

(40) H H H S 5

(41) H H H S 5

(42) H H H S 5

(43) H H H — 5

(44) Cl Cl H — 5

(45) CH₃ CH₃ H — 5

(46) NO₂ H H — 5

(47) H H H — 7

(48) H H H — 11 

(49) H H H S 5

(50) H H H S 5

(51) H H H S 5

(52) H H H S 5

(53) H H H S 5

(54) H H H S 5

(55) H H H S 5

(56) H H H S 5

(57) H H H S 5

(58) Cl Cl H S 5

(59) H H H S 5

(60) H H H S 5

(61) H H H S 5

(62) H H H S 5

(63) H H H S 5

(64) H H CH₃ S 5

(65) H H COC₂H₅ S 5

(66) SO₂NHCH₃ H CH₃ S 5

No. R¹¹ R¹² R² Y l Q (67) H H H S 1

(68) H H H S 2

The compounds of the present invention represented by the aforementionedformulas (IA) and (IB) may form acid addition salts. In addition, whereR¹ and/or R² are hydroxyl groups in the compounds of the formula (IA),or where R⁵ is hydroxyl group in the compounds of formula (IB), thecompounds may form base addition salts. Both of these acid additionsalts and base addition salts fall within the scope of the presentinvention. Furthermore, where R¹ and/or R² are hydroxyl groups in thecompounds of the formula (IA), or where R⁵ is hydroxyl group in thecompounds of formula (IB), the compounds may exist as intramolecularzwitterion-type compounds. These compounds also fall within the scope ofthe present invention. Examples of the acid addition salts include, forexample, mineral acid salts such as hydrochlorides, hydrobromides,nitrates, sulfates, or phosphates, or organic acid salts such asp-toluenesulfonates, methanesulfonates, oxalates, tartrates, malates, orcitrates. Examples of the base addition salts include, for example,metal salts such as sodium salts, potassium salts, magnesium salts, orcalcium salts, ammonium salts, triethylamine salts or the like.

The compounds of the present invention may have one or more asymmetriccarbon atoms depending on the sorts of substituents R¹ to R⁶. In thatcase, optical isomers based on one or more asymmetric carbon atoms ordiastereoisomers based on two or more asymmetric carbon atoms may exist,and both of the optical isomers and diastereoisomers in pure forms fallwithin the scope of the present invention. In addition, any mixtures ofthe optical isomers in an arbitrary ratio, racemates, and any mixturesthe diastereoisomers in an arbitrary ratio also fall within the scope ofthe present invention. It should also be understood that any hydrate ora solvate of the compound of the present invention in free form or in aform of a salt falls within the scope of the present invention.

The compounds of the present invention can be prepared according to thereaction schemes set out below by reactions well known to those skilledin the art by using a readily available compound of the formula (II) asstarting material. Specific methods for the reactions will be detailedin the working examples set out in the specification. Therefore, thoseskilled in the art can easily prepare the compounds of the presentinvention by referring to the general explanation and examples mentionedbelow, and if necessary, by making suitable alterations and/ormodifications to these methods. In the schemes, R¹, R², R³, R⁵, R⁶, n,m, Z, Y, and L have the same meanings as those defined above, X₁represents a leaving group for nucleophilic substitution reaction suchas a halogen atom or an alkyl- or arylsulfonyloxy group, and X₂represents a leaving group as mentioned above, carboxyl group, or analkoxycarbonyl group.

Among the 2-mercaptobenzimidazole compounds of the formula (II) used forthe preparation of the compounds of the formula (IV), any compoundsalready known can be prepared by the methods described in respectiveliteratures. Novel compounds can generally be prepared by the methoddescribed in Org. Syn. Col. Vol. 4, p.569. Some of the compounds arecommercially available as reagents. A compound of the formula (IV) canbe prepared by reacting a compound of the formula (II) with a reagentfor introducing a linking group (X₁-L-X₂; III). This reaction maygenerally be performed in, for example, in a common organic solvent suchas ethanol, acetonitrile, acetone, ethyl acetate, dimethylformamide(DMF), or tetrahydrofuran (THF).

The reaction may be performed in the presence of a base catalyst as anacid scavenger such as sodium hydroxide, potassium carbonate,triethylamine, or sodium ethylate, if necessary. The reaction can alsosufficiently proceed in an alcohol by heating without a catalyst. When abase is used, a reaction temperature may be appropriately chosendepending on the sorts of reactants and a solvent. Generally, thereaction may be performed at a temperature of 0-150° C., preferably20-100° C. When the reaction is carried out in an alcohol withoutcatalyst, a temperature of 50-120° C. is preferable.

When both of X₁ and X₂ are leaving groups, it is preferred to use anexcess amount of compound of the formula (III) based on a compound ofthe formula (II) in order to avoid any side reactions. Generally, a 2-to 10-fold amount, preferably a 4- to 10-fold amount may be applied.After the completion of the reaction, unreacted compound of the formula(III) can generally be recovered. On the other hand, when X₂ is carboxylgroup or an alkoxycarbonyl group, an approximately equimolar amount of acompound of the formula (III) should be used based on a compound theformula (II) to avoid side reactions. For example, it is preferable touse an approximately 0.8-1.2 moles, more preferably 0.95-1.1 moles of acompound of the formula (III) based on a compound of the formula (II).When X₂ is carboxyl group, a carboxylic acid compound of the formula(IV) produced after the completion of the reaction can be isolated byneutralization and then collection by filtration or extraction with anorganic solvent.

When X₂ is a leaving group such as chlorine atom, bromine atom, orp-toluenesulfonyloxy group, a compound of the formula (IV) can besubjected to reaction with a 2-mercaptoazole compound of the formula (V)to produce a compound of the formula (IA) of the present invention (acompound of the formula 2 in the above scheme). The compound of theformula (V) used as a reactant in this step can generally be produced bya known method (Org. Syn. Col. Vol., 4, p.569). Some of the compoundscan be obtained as commercial products. The reaction between a compoundof the formula (IV) and a compound of the formula (V) can be performedunder conditions similar to those for the reaction of the compound ofthe formula (II) and a compound of the formula (III).

When X₂ is carboxyl group or an alkoxycarbonyl group, a compound of theformula (IV) can be reacted with an o-phenylenediamine compound of theformula (VI) to prepare a compound of the present invention (a compoundof the formula 3 in the scheme). The compound of the formula (VI) can beeasily obtained as a commercial product. The condensation-cyclizationreaction of a compound of the formula (IV) and a compound of the formula(VI) can generally be performed in the presence of an acid catalyst. Asthe acid catalyst, for example, hydrochloric acid, hydrobromic acid,sulfric acid, phosphoric acid, an organic sulfonic acid such asp-toluenesulfonic acid or the like can suitably be used. This reactioncan be performed without a solvent, or in the presence of water or anorganic solvent chosen from various types. A molar ratio of a compoundof the formula (VI) based on a compound of the formula (IV) maypreferably be 0.8-1.2 and most preferably 0.95-1.1. The acid catalystcan be used in an amount of about 0.1- to 10 moles, preferably 1- to 5moles based on a compound of the formula (IV).

In the above reactions, when R³ is hydrogen atom, different types of thecompounds of the present invention can be produced by subjecting astarting compound of the formula (II) or a compound of the formula 2 orthe formula 3 to alkylation or acylation. The alkylation can beperformed by reaction with a reactive alkylating agent such as alkylhalides and alkyl tosylates using a base catalyst such as sodiumhydroxide, potassium carbonate, triethylamine, or sodium ethylate as anacid scavenger in an ordinary organic solvent as mentioned above. Areaction temperature can be appropriately chosen depending on a type ofa compound as a reactant and a solvent. Generally, the reaction ispreferably performed at a temperature of about 0-100° C., preferablyabout 20-60° C.

The acylation can generally be performed by reaction with acorresponding acid halide in the presence of a base catalyst such aspotassium carbonate, triethylamine, or pyridine as an acid scavenger inan ordinary inert solvent. As the inert solvent, for example,acetonitrile, ethyl acetate, THF, DMF, dimethylacetamide (DMAc) or thelike may be used. When strongly polar DMF, DMAc, acetonitrile or thelike is used, the reaction proceeds even in the absence of a basecatalyst. The acid halide is preferably used in 1.8- to 2.4 moles basedon a compound as a reactant. The reaction may be carried out at areaction temperature of about 30-150° C., preferably about 50-100° C.

The compounds represented by the formula (IB) can be prepared in asimilar manner to the preparation of the compounds represented by theformula (IA). When X₂ is a leaving group such as chlorine atom, bromineatom, or p-toluenesulfonyloxy group, a compound of the formula (IV) canbe subjected to reaction with a 2-mercapto-substituted heterocycliccompound (VII) to produce a compound of the present invention (acompound of the formula 4 in the above scheme). A compound of theformula (VII) used in this step can generally be produced by a knownmethod, and some of the compounds can be obtained as commercialproducts. The reaction between a compound of the formula (IV) and acompound of the formula (VII) can be performed in a similar manner tothe reaction of a compound of the formula (II) and a compound of theformula (III).

A compound of the formula (VIII), which is obtained by reacting a2-mercapto-substituted heterocyclic compound of the formula (VII) withan excess amount of an agent (III) for the formation of a linking groupaccording to the scheme mentioned above, may be used as a syntheticintermediate for the preparation of the compound of the presentinvention. The above reaction for the preparation of a compound of theformula (VIII) can be performed in a similar manner to the reaction ofcompounds of the formula (II) and the formula (III). When X² is ahalogen atom or an alkyl- or arylsulfonyloxy group, a compound of thepresent invention can be produced by reacting a compound of the formula(VIII) with a 2-mercaptobenzimidazole of the formula (IX). This reactioncan be carried out in a similar manner to the reaction of compounds ofthe formula (IV) and the formula (V). A 2-mercaptobenzimidazole compoundof the formula (IX) can be prepared by a known method, and some of thecompounds can be obtained as commercial products.

When X₂ is carboxyl group or an alkoxycarbonyl group, a compound of thepresent invention can be prepared by reacting a compound of the formula(VIII) with an o-phenylenediamine of the formula (X). This reaction canbe performed in a similar manner to the reaction of a compound of theformula (IV) and an o-phenylenediamine of the formula (VI). In thisreaction, when R⁶ is hydrogen atom, other compounds of the presentinvention can be produced by subjecting a starting compound of theformula (II), or a compound of the formula 4, 6 or 7 to alkylation oracylation reaction. The alkylation and the acylation reaction can beperformed as described above.

The compounds of the present invention have a potent activity ofsuppressing the foaming of macrophages which is involved in theformation of arterial sclerosis lesions in arterial sclerosis.Therefore, the compounds are useful as an active ingredient of amedicament for preventive and/or therapeutic treatment of arterialsclerosis, and an active ingredient of a medicament for preventiveand/or therapeutic treatment of hyperlipemia by lowering bloodcholesterol. According to further aspects of the present invention,there are thus provided a preventive and/or therapeutic medicament forarterial sclerosis, and preventive and/or therapeutic medicament forhyperlipemia each contains the aforementioned compound as an activeingredient.

Although it is not intended to be bound by any specific theory, it hasbeen known that invasion of foamed macrophages into arterial wallstriggers hyperplasia of smooth muscles of arterial walls, therebycausing arterial sclerosis (Schaffner, T. et al., Amer. J. Pathol., 110,pp.57-73, 1980; Gerrity, R. G., Amer. J. Pathol. 103, pp.181-190, 1981).The medicaments of the present invention directly inhibit the formationof arterial sclerosis lesions and enables retraction of arterialsclerosis lesions by suppressing the foaming of macrophages which isinvolved in the formation of arterial sclerosis lesions. Accordingly,the medicaments of the present invention are useful for preventionand/or treatment of arterial sclerosis and hyperlipemia brought byvarious causes.

Route of administration of the medicament of the present invention isnot particularly limited, and the medicament can be administered orallyor parenterally. The compound of the formula (IA) or (IB) as an activeingredient, per se, can be used as the medicament of the presentinvention. Generally, however, it is preferred that pharmaceuticalpreparations in forms well known to those skilled in the art areprovided in which a compound of the formula (IA) or (IB) as activeingredient is added with a pharmacologically and pharmaceuticallyacceptable additive. Examples of formulations suitable for oraladministration include, for example, tablets, capsules, powders,subtilized granules, granules, liquids, syrups and the like. Examples offormulations suitable for parenteral administration include, forexample, injections, drip infusions, suppositories, inhalants,formulations for percutaneous absorption, formulations for transmucosalabsorption, patches and the like. Examples of pharmacologically andpharmaceutically acceptable additives include excipients, disintegratorsor disintegrating agents, binders, lubricants, coating agents,colorants, diluents, base materials, dissolving agents or dissolvingaids, isotonic agents, pH modifiers, stabilizers, propellants, adhesivesand the like.

Pharmaceutical preparations suitable for oral, percutaneous, ortransmucosal administration can be manufactured by using, aspharmacologically or pharmaceutically acceptable additives, for example,excipients such as glucose, lactose, D-mannitol, starch, or crystallinecellulose; disintegrators or disintegrating aids such ascarboxymethylcellulose, starch or carboxymethylcellulose calcium;binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, or gelatin; lubricants such as magnesium stearateor talc; coating agents such as hydroxypropylmethylcellulose,saccharose, polyethylene glycol, or titanium oxide; base materials suchas petrolatum, liquid paraffin, polyethylene glycol, gelatin, chinaclay, glycerin, purified water, or hard fat; propellants such as flons,diethyl ether, or compressed gases; adhesives such as sodiumpolyacrylate, polyvinyl alcohol, methylcellulose, polyisobutylene, orpolybutene; base cloths such as cotton cloth and plastic sheets, and thelike.

Pharmaceutical compositions suitable as injections and drip infusionsmay contain pharmaceutical additives, for example, dissolving agents ordissolving aids such as distilled water for injection, physiologicalsaline and propylene glycol which can form aqueous injections orinjections to be dissolved upon use; isotonic agents such as glucose,sodium chloride, D-mannitol and glycerin; pH modifiers such as inorganicacids, organic acids, inorganic bases, and organic bases and the like.

Dose of the medicament of the present invention is not particularlimited, and a dose can be appropriately chosen depending on the routeof administration, purpose of preventive and/or therapeutic treatment,age, body weight, and symptoms of a patient and the like. For example, adose for intravenous administration for an adult may be about 10-400 mg,preferably about 10-100 mg per day as an active ingredient, and for oraladministration, a dose for an adult may be about 10-800 mg, preferablyabout 10-300 mg per day as an active ingredient. The medicament of thepresent invention may be administered once a day or several times a dayas divided portions. Administration period can also be appropriatelychosen depending on the age of a patient, improvement of symptoms andthe like.

EXAMPLES

The present invention will be explained more specifically by referringto the following examples. However, the scope of the present inventionis not limited to these examples. In the examples, the indications suchas “Example A1” and “Example B 1” correspond to the methods ofpreparation of the compounds embraced by the general formula (A1) and(B1), respectively. Compound numbers such as “Compound A1” and “CompoundB1” correspond to the numbers of the compounds whose chemical structuresare shown as particularly preferred compounds of the present invention.

Example A1 Synthesis of 5-(2′-benzimidazolylthio)pentyl bromide

2-Mercaptobenzimidazole (6.0 g) and 1,5-dibromopentane (60 g) weredissolved in ethanol (50 ml), and the solution was heated under refluxfor six hours. After the solvent was evaporated under reduced pressure,the residue was added with ethyl acetate (50 ml) and hexane (50 ml) fordigestion to obtain about 12 g of solid. Water (100 ml) was added to thesolid, and the mixture was neutralized with aqueous sodium hydroxide.The deposited oil-soluble product was extracted with ethyl acetate, andthe extract was concentrated after washing with water. The residue wasapplied to silica gel column chromatography (silica gel 220 g, solvent:chloroform) to obtain crude crystals (8.7 g). These crude crystals wererecrystallized from ethanol to obtain the title compound (7.8 g).

Melting point: 126-127° C. Elemental analysis: as C₁₂H₁₅N₂SBrCalculated: C, 48.15; H, 5.05; N, 9.36 (%) Found: C, 47.98; H, 5.11; N,9.21 (%)

Example A2 Synthesis of1-(2′-(5′-methylbenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(Compound A1)

5-(2′-Benzimidazolylthio)pentyl bromide (0.57 g) and2-mercapto-5-methyl-benzimidazole (0.36 g) were dissolved in ethanol (5ml), and the solution was heated under reflux for eight hours. Aftercooling, the reaction mixture was neutralized with aqueous sodiumhydroxide, and the deposited oily product was extracted with ethylacetate. After the extract was washed with water, the solvent wasevaporated under reduced pressure, and the resulting oily product wasseparated and purified by silica gel column chromatography. Theresulting crude product was crystallized from ethyl acetate to obtainthe title compound (0.52 g).

Melting point: 163-165° C. Elemental analysis: as C₂₀H₂₂N₄S₂ Calculated:C, 62.79; H, 5.80; N, 14.65 (%) Found: C, 62.58; H, 5.71; N, 14.51 (%)

Example A3 Synthesis of1-(2′-(5′-chlorobenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(Compound A2)

In the same manner as in Example A2, 0.61 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.6 g) and5-chloro-2-mercaptobenzimidazole (0.37 g).

Melting point: 160-163° C. Elemental analysis: as C₁₉H₁₉N₄S₂ClCalculated: C, 56.63; H, 4.75; N, 13.91 (%) Found: C, 56.49; H, 4.60; N,13.71 (%)

Example A4 Synthesis of1-(2-(5′-chlorobenzimidazolyl)thio)-5-(2″-(5″-methylbenzimidazolyl)thio)pentane(Compound A3)

In the same manner as in Example A1,5-(2-(5′-methylbenzimidazolyl)thio)pentyl bromide was synthesized from2-mercapto-5-methylbenzimidazole and 1,5-dibromopentane. In the samemanner as in Example A3, 0.6 g of the title compound was obtained(crystallized from ethanol/actonitrile) from the resulting5-(2-(5′-methylbenzimidazolyl)thio)pentyl bromide (0.63 g) and5-chloro-2-mercapto-benzimidazole (0.37 g).

Melting point: 174-175° C. Elemental analysis: as C₂₀H₂₁N₄S₂ClCalculated: C, 57.60; H, 5.08; N, 13.44 (%) Found: C, 57.44; H, 5.14; N,13.58 (%)

Example A5 Synthesis of1-(2′-(5′-methoxybenzimidazolyl)thio)-5-(2″-(5″-methylbenzimidazolyl)thio)pentane(Compound A4)

In the same manner as in Example A4, 0.7 g of the title compound wasobtained (crystallized from ethyl acetate) from5-(2′-(5′-methylbenzimidazolyl)thio)pentyl bromide (0.63 g) and2-mercapto-5-methoxybenzimidazole (0.36 g).

Melting point: 170-171° C. Elemental analysis: as C₂₁H₂₄N₄OS₂Calculated: C, 61.13; H, 5.86; N, 13.58 (%) Found: C, 60.98; H, 5.74; N,13.42 (%)

Example A6 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-(5″-methoxybenzimidazolyl)thio)pentane(Compound A5)

In the same manner as in Example A2, 0.89 g of the title compound(wax-like material) was obtained from 5-(2′-benzimidazolylthio)pentylbromide (0.9 g) and 2-mercapto-5-methoxybenzimidazole (0.57 g).

Example A7 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-(5″-hydroxybenzimidazolyl)thio)pentane(Compound A6)

Compound A5 (0.34 g) was dissolved in hydrobromic acid (2 ml) and water(2 ml), and the solution was heated under reflux for 16 hours. Thereaction mixture was neutralized with aqueous sodium hydroxide, and thenextracted with ethyl acetate. The extract was washed with water, and thesolvent was evaporated under reduced pressure. The residue wascrystallized from ethanol/ethyl acetate to obtain the title compound(0.18 g).

Melting point: 112-114° C. Elemental analysis: as C₁₉H₂₀N₄OS₂Calculated: C, 59.35; H, 5.24; N, 14.57 (%) Found: C, 59.21; H, 5.12; N,14.39 (%)

Example A8 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-(5″-methanesulfonylamino-benzimidazolyl)thio)pentane(Compound A7)

In the same manner as in Example A2, 0.32 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and2-mercapto-5-methanesulfonylaminobenzimidazole (0.28 g).

Melting point: 141-143° C. Elemental analysis: as C₂₀H₂₃N₅O₂S₃Calculated: C, 52.03; H, 5.02; N, 15.18 (%) Found: C, 51.84; H, 4.98; N,15.09 (%)

Example A9 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-(5″-propionylaminobenzimidazolyl)thio)pentane(Compound A8)

In the same manner as in Example A2, 0.23 g of the title compound(wax-like product) was obtained from 5-(2′-benzimidazolylthio)pentylbromide (0.3 g) and 2-mercapto-5-methanesulfonylaminobenzimidazole (0.22g).

Example A10 Synthesis of1-(2′-(5′-ethoxycarbonylbenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(Compound A9)

In the same manner as in Example A2, 0.14 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and2-mercapto-5-ethoxycarbonylbenzimidazole (0.22 g).

Melting point: 155-156° C. Elemental analysis: as C₂₂H₂₄N₄O₂S₂Calculated: C, 59.97; H, 5.49; N, 12.72 (%) Found: C, 59.73; H, 5.38; N,12.58 (%)

Example A11 Synthesis of1-(2′-(5′,6′-dimethylbenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(Compound A10)

In the same manner as in Example A2, 0.54 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.6 g) and2-mercapto-5,6-dimethylbenzimidazole (0.35 g).

Melting point: 150-153° C. Elemental analysis: as C₂₁H₂₄N₄S₂ Calculated:C, 63.60; H, 6.10; N, 14.13 (%) Found: C, 63.36; H, 6.02; N, 14.32 (%)

Example A12 Synthesis of1-(2′-(5′,6′-dichlorobenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(Compound A11)

In the same manner as in Example A2, 0.72 g of the title compound wasobtained (crystallized from acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.6 g) and5,6-dichloro-2-mercaptobenzimidazole (0.44 g).

Melting point: 167-169° C. Elemental analysis: as C₁₉H₁₈N₄S₂Cl₂Calculated: C, 52.17; H, 4.15; N, 12.81 (%) Found: C, 52.03; H, 4.01; N,12.62 (%)

Example A13 Synthesis of 6-(2′-benzimidazolylthio)hexyl bromide

In the same manner as in Example A1, 5.0 g of the title compound wasobtained (crystallized from ethyl acetate/hexane) from2-mercaptobenzimidazole (3.0 g) and 1,6-dibromohexane (24.4 g).

Example A14 Synthesis of1-(2′-(5′,6′-dichlorobenzimidazolyl)thio)-6-(2″-benzimidazolylthio)hexane(Compound A12)

In the same manner as in Example A2, 0.39 g of the title compound wasobtained (crystallized from ethyl acetate/chloroform) from6-(2′-benzimidazolylthio)hexyl bromide (0.31 g) and5,6-dichloro-2-mercaptobenzimidazole (0.22 g).

Melting point: 287-230° C. Elemental analysis: as C₂₀H₂₀N₄S₂Cl₂Calculated: C, 53.21; H, 4.47; N, 12.41 (%) Found: C, 53.07; H, 4.22; N,12.12 (%)

Example A15 Synthesis of 8-(2′-benzimidazolylthio)octyl bromide

In the same manner as in Example A1, 2.6 g of the title compound wasobtained (crystallized from ethyl acetate/hexane) from2-mercaptobenzimidazole (1.5 g) and 1,8-dibromooctane (13.6 g).

Example A16 Synthesis of1-(2′-(5′,6′-dichlorobenzimidazolyl)thio)-8-(2″-benzimidazolylthio)octane(Compound A13)

In the same manner as in Example A2, 0.36 g of the title compound wasobtained (crystallized from ethanol/water) from8-(2′-benzimidazolylthio)octyl bromide (0.37 g) and5,6-dichloro-2-mercaptobenzimidazole (0.22 g).

Melting point: 176-178° C. Elemental analysis: as C₂₂H₂₄N₄S₂Cl₂Calculated: C, 55.11; H, 5.05; N, 11.69 (%) Found: C, 54.98; H, 4.88; N,11.43 (%)

Example A17 Synthesis of1-(2′-(5′,6′-dichlorobenzimidazolyl)thio)-5-(2″-(5″-methylbenzimidazolyl)thio)pentane(Compound A14)

In the same manner as in Example A2, 0.32 g of the title compound wasobtained (crystallized from acetonitrile) from5-(2′-(5′-methylbenzimidazolyl)thio)pentyl bromide (0.32 g) and5,6-dichloro-2-mercaptobenzimidazole (0.24 g).

Melting point: 161-165° C. Elemental analysis: as C₂₀H₂₀N₄S₂Cl₂Calculated: C, 53.21; H, 4.47; N, 12.41 ( %) Found: C, 53.10; H, 4.29;N, 12.21 (%)

Example A18 Synthesis of1-(2′-(5′,6′-dichlorobenzimidazolyl)thio)-5-(2″-(5″,6″-dimethylbenzimidazolyl)thio)pentane(Compound A15)

In the same manner as in Example A1,5-(2′-(5′,6′-dimethylbenzimidazolyl)thio)pentyl bromide (6.6 g) wasobtained from 2-mercapto-5,6-dimethylbenzimidazole (5.34 g) and 1,5-dibromopentane (34.5 g). Furthermore, in the same manner as in ExampleA2, 0.72 g of the title compound was obtained (crystallized fromacetonitrile) from 5-(2′-(5′,6′-dimethylbenzimidazolyl)thio)pentylbromide (0.65 g) and 5,6-dichloro-2-mercaptobenzimidazole (0.44 g).

Melting point: 171-173° C. Elemental analysis: as C₂₁H₂₂N₄S₂Cl₂Calculated: C, 54.19; H, 4.76; N, 12.04 (%) Found: C, 54.03; H, 4.57; N,12.11 (%)

Example A19 Synthesis of1-(2′-(5′-chloro-6′-trifluoromethylbenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(Compound A16)

In the same manner as in Example A2, 0.29 g of the title compound(wax-like material) was obtained from 5-(2′-benzimidazolylthio)pentylbromide (0.3 g) and 5-chloro-2-mercapto-6-trifluoromethylbenzimidazole(0.26 g).

Example A20 Synthesis of1-(2′-(5′-cyanobenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(Compound A17)

In the same manner as in Example A2, 0.22 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and5-cyano-2-mercaptobenzimidazole (0.16 g).

Melting point: 152-154° C. Elemental analysis: as C₂₀H₁₉N₅S₂ Calculated:C, 61.04; H, 5.22; N, 17.80 (%) Found: C, 59.96; H, 5.10; N, 17.64 (%)

Example A21 Synthesis of 4-(2′-benzimidazolylthio)butyl chloride

In the same manner as in Example A1, 6 g of the title compound (wax-likematerial) was obtained from 2-mercaptobenzimidazole (6.2 g) and1,4-chlorobromobutane (10.3 g).

Example A22 Synthesis of1-(2′-(5′-methylbenzimidazolyl)thio)-4-(2″-benzimidazolylthio)butane(Compound A18)

In the same manner as in Example A2, 0.09 g of the title compound wasobtained (crystallized from methanol/water) from4-(2′-benzimidazolylthio)butyl chloride (0.33 g) and5-methyl-2-mercaptobenzimidazole (0.24 g).

Melting point: 204-206° C. Elemental analysis: as C₁₉H₂₀N₄S₂ Calculated:C, 61.92; H, 5.47; N, 15.21 (%) Found: C, 61.78; H, 5.34; N, 15.10 (%)

Example A23 Synthesis of1-(2′-(5′-methylbenzimidazolyl)thio)-6-(2″-benzimidazolylthio)hexane(Compound A19)

In the same manner as in Example A2, 0.33 g of the title compound wasobtained (crystallized from ethyl acetate) from6-(2′-benzimidazolylthio)hexyl bromide (0.31 g) and5-methyl-2-mercaptobenzimidazole (0.16 g).

Melting point: 202-204° C. Elemental analysis: as C₂₁H₂₄N₄S₂ Calculated:C, 63.60; H, 6.16; N, 14.13 (%) Found: C, 63.42; H, 6.09; N, 14.01 (%)

Example A24 Synthesis of1-(2′-(5′-methylbenzimidazolyl)thio)-8-(2″-benzimidazolylthio)octane(Compound A20)

In the same manner as in Example A2, 0.36 g of the title compound wasobtained (crystallized from ethyl acetate/hexane) from8-(2′-benzimidazolylthio)octyl bromide (0.37 g) and5-methyl-2-mercaptobenzimidazole (0.16 g).

Melting point: 101-103° C. Elemental analysis: as C₂₃H₂₈N₄S₂ Calculated:C, 65.05; H, 6.65; N, 13.20 (%) Found: C, 64.87; H, 6.41; N, 13.34 (%)

Example A25 Synthesis of2-(2-(2-p-toluenesulfonyloxy)ethoxy)ethylmercaptobenzimidazole

2-Mercaptobenzimidazole (3.1 g) and diethylene glycol di-p-tosylate (8.3g) were heated under reflux in acetonitrile for 18 hours. After thesolvent was evaporated under reduced pressure, 2.4 g of the titlecompound (wax-like material) was separated from the residue by silicagel column chromatography.

Example A26 Synthesis of2-(2-(2-(2′-(5′-methylbenzimidazolyl)thio)ethoxy)ethylmercaptobenzimidazole(Compound A21)

In the same manner as in Example A1, 0.21 g of the title compound wasobtained from2-(2-(2-p-toluenesulfonyloxy)ethoxy)ethylmercaptobenzimidazole (0.38 g)and 2-mercapto-5-methylbenzimidazole (0.17 g)

Melting point: 130-131° C. Elemental analysis: as C₁₉H₂₀N₄OS₂Calculated: C, 59.35; H, 4.96; N, 14.57 (%) Found: C, 59.12; H, 4.72; N,14.32 (%)

Example A27 Synthesis of2-(2-(2-(2-p-toluenesulfonyloxy)ethoxy)ethoxy)ethylmercaptobenzimidazole

2-Mercaptobenzimidazole (3.1 g) and triethylene glycol di-p-tosylate(9.6 g) were heated under reflux in acetonitrile for 18 hours. Thesolvent was evaporated under reduced pressure, and 3.3 g of the titlecompound (wax-like material) was separated from the residue by silicagel column chromatography.

Example A28 Synthesis of2-(2-(2-(2-(2′-(5′-methylbenzimidazolyl)thio)ethoxy)ethoxy)ethylmercaptobenzimidazole(Compound A22)

In the same manner as in Example A1, 0.33 g of the title compound wasobtained from2-(2-(2-(2-p-toluenesulfonyloxy)ethoxy)ethoxy)ethylmercaptobenzimidazole(0.43 g) and 2-mercapto-5-methylbenzimidazole (0.17 g)

Melting point: 119-122° C. Elemental analysis: as C₂₁H₂₄N₄O₂S₂Calculated: C, 58.85; H, 5.64; N, 13.08 (%) Found: C, 58.59; H, 5.45; N,12.89 (%)

Example A29 Synthesis of1-(2′-(1′-methyl-5′-methylsulfamoylbenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(Compound A23)

In the same manner as in Example A2, 0.22 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and2-mercapto-1-methyl-5-methylsulfamoylbenzimidazole (0.26 g).

Melting point: 139-140° C. Elemental analysis: as C₂₁H₂₅N₅O₂S₃Calculated: C, 53.03; H, 5.30; N, 14.73 (%) Found: C, 52.92; H, 5.13; N,14.61 (%)

Example A30 Synthesis of1-(2′-(1′-methyl-5′-methylsulfamoylbenzimidazolyl)thio)-5-(2″-(1-propionyl)benzimidazolyl)thio)pentane (Compound A25)

1-(2′-(1′-Methyl-5′-methylsulfamoylbenzimidazolyl)thio)-5-(2″-benzimidazolylthio)pentane(0.1 g) was dissolved in a mixture of dimethylacetamide (0.3 ml),acetonitrile (0.5 ml) and triethylamine (0.1 ml), and the mixture wasslowly added with propionyl chloride (4 ml) at 45° C. After stirring wascontinued for 4.5 hours, the mixture was added with water and thenextracted with ethyl acetate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography, and then crystallized from ethyl acetate/acetonitrile toobtain 0.04 g of the title compound.

Melting point: 91-93° C. Elemental analysis: as C₂₄H₂₉N₅O₃S₃ Calculated:C, 54.21; H, 5.50; N, 13.17 (%) Found: C, 54.11; H, 5.32; N, 13.02 (%)

Example A31 Synthesis of ethyl 6-(2-benzimidazolylthio)caproate

2-Mercaptobenzimidazole (6.3 g) and 6-bromocaproic acid (7.8 g) weredissolved in ethanol (35 ml), and the solution ws heated under refluxfor 12 hours. After cooling, the reaction was added with water, and themixture was adjusted to pH 8 with aqueous sodium carbonate. Thedeposited crystals were collected by filtration, and dried to obtain11.2 g of the title compound.

Example A32 Synthesis of2-(5-(2′-benzimidazolylthio)pentyl)benzimidazole (Compound A27)

Ethyl 6-(2-benzimidazolylthio)caproate (0.88 g) and o-phenylenediamine(0.34 g) were dissolved in concentrated hydrochloric acid (1 ml) andwater (2 ml), and the mixture was heated under reflux under nitrogenflow for 20 hours. After cooling, the reaction mixture was added withwater (3 ml), and the precipitates were collected by filtration. Theprecipitates were suspended in water/methanol (1:1), and aqueous sodiumhydroxide was added to the suspension so as to be maintained at pH 8.The deposited crystals were collected by filtration and washed withwater-containing methanol until they became neutral to obtain 0.88 g ofthe title compound.

Melting point: 313-316° C. Elemental analysis: as C₁₉H₂₀N₄S Calculated:C, 67.82; H, 5.99; N, 16.66 (%) Found: C, 67.65; H, 5.72; N, 16.52 (%)

Example A33 Synthesis of1-propionyl-2-(5-(2′-(1-propionylbenzimidazolyl)thio)pentyl)benzimidazole(Compound A24)

In the same manner as in Example A30, 0.17 g of the title compound wasobtained from 2-(5-(2′-benzimidazolylthio)pentyl)benzimidazole (0.2 g).

Melting point: 142-145° C. Elemental analysis: as C₂₅H₂₈N₄O₂SCalculated: C, 66.93; H, 6.29; N, 12.49 (%) Found: C, 66.76; H, 6.11; N,12.22 (%)

Example A34 Synthesis of1-methyl-2-(5-(2′-(1-methylbenzimidazolyl)thio)pentyl)benzimidazole(Compound A26)

2-(5-(2′-Benzimidazolylthio)pentyl)benzimidazole (0.2 g) was dissolvedin dimethylformamide (2 ml), and the solution was added with potassiumcarbonate (0.18 g) and methyl iodide (0.3 g), and then the mixture wasstirred at 40° C. for 14 hours. After cooling, the reaction was addedwith water, and then extracted with ethyl acetate. After the extract waswashed with water, the solvent was evaporated under reduced pressure,and the residue was crystallized from ethyl acetonitrile to obtain 0.03g of the title compound.

Melting point: 118-120° C. Elemental analysis: as C₂₁H₂₄N₄S Calculated:C, 69.19; H, 6.64; N, 15.31 (%) Found: C, 69.03; H, 6.41; N, 15.23 (%)

Example A35 Synthesis of2-(5-(2′-benzimidazolylthio)pentyl)-5,6-dimethylbenzimidazole (CompoundA28)

In the same manner as in Example A32, 0.70 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from ethyl6-(2-benzimidazolylthio)caproate (0.88 g) and4,5-dimethyl-o-phenylenediamine (0.43 g).

Melting point: 211-214° C. Elemental analysis: as C₂₁H₂₄N₄S Calculated:C, 69.19; H, 6.64; N, 15.31 (%) Found: C, 69.11; H, 6.48; N, 15.12 (%)

Example A36 Synthesis of2-(5-(2′-benzimidazolylthio)pentyl)-5,6-dichlorobenzimidazole (CompoundA28)

In the same manner as in Example A32, 0.93 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from ethyl6-(2-benzimidazolylthio)caproate (0.88 g) and4,5-dichloro-o-phenylenediamine (0.56 g).

Melting point: 194-196° C. Elemental analysis: as C₁₉H₁₈N₄SCl₂Calculated: C, 56.30; H, 4.48; N, 13.83 (%) Found: C, 56.24; H, 4.37; N,13.69 (%)

Example A37 Synthesis of2-(5-(2′-benzimidazolylthio)pentyl)-5-nitrobenzimidazole (Compound A29)

In the same manner as in Example A32, 0.50 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from ethyl6-(2-benzimidazolylthio)caproate (0.88 g) and 4-nitro-o-phenylenediamine(0.48 g).

Melting point: 184-185° C. Elemental analysis: as C₁₉H₁₉N₅O₂SCalculated: C, 59.82; H, 5.02; N, 18.36 (%) Found: C, 59.59; H, 4.98; N,18.44 (%)

Example A38 Synthesis of2-(7-(2′-benzimidazolylthio)heptyl)benzimidazole (Compound A31)

In the same manner as in Example A31, 6.4 g of ethyl8-(2-benzimidazolylthio)octanoate was obtained from2-mercaptobenzimidazole (3.1 g) and 8-bromooctanoic acid (4.46 g). Then,in the same manner as in Example A32, 0.70 g of the title compound wasobtained from ethyl 8-(2-benzimidazolylthio)octanoate (0.96 g) ando-phenylenediamine (0.34 g).

Melting point: 263-264° C. Elemental analysis: C₂₁H₂₄N₄S Calculated: C,69.19; H, 6.64; N, 15.37 (%) Found: C, 69.03; H, 6.48; N, 15.21 (%)

Example A39 Synthesis of2-(11-(2′-benzimidazolylthio)undecyl)benzimidazole (Compound A32)

In the same manner as in Example A31, 6.4 g of ethyl12-(2-benzimidazolylthio)dodecanoate was obtained from2-mercaptobenzimidazole (3.1 g) and 12-bromododecanoic acid (5.3 g).Then, in the same manner as in Example A32, 0.70 g of the title compoundwas obtained from ethyl 11-(2-benzimidazolylthio)dodecanoate (1.13 g)and o-phenylenediamine (0.34 g).

Melting point: 206-208° C. Elemental analysis: as C₂₅H₃₂N₄S Calculated:C, 71.39; H, 7.67; N, 13.32 (%) Found: C, 71.22; H, 7.41; N, 13.19 (%)

Example A40 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-benzothiazolylthio)pentane (CompoundA33)

In the same manner as in Example A2, 0.2 g of the title compound wasobtained (crystallized from acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and2-mercaptobenzothiazole (0.17 g).

Melting point: 124-125° C. Elemental analysis: as C₁₉H₁₉N₃S₃ Calculated:C, 59.19; H, 4.97; N, 10.90 (%) Found: C, 59.31; H, 4.75; N, 10.70 (%)

Compound A36 was also synthesized in a similar manner.

Example A41 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-(5″-chlorobenzothiazolyl)thio)pentane(Compound A34)

In the same manner as in Example A2, 0.38 g of the title compound wasobtained (crystallized from acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and5-chloro-2-mercaptobenzothiazole (0.20 g).

Melting point: 125-127° C. Elemental analysis: as C₁₉H₁₈N₃S₃ClCalculated: C, 54.33; H, 4.32; N, 10.01 (%) Found: C, 54.11; H, 4.12; N,10.12 (%)

Example A42 Synthesis of 1-(2′-benzimidazolylthio)-5-(2″-(6″-ethoxybenzothiazolyl)thio)pentane (Compound A35)

In the same manner as in Example A2, 0.38 g of the title compound wasobtained (crystallized from acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and6-ethoxy-2-mercaptobenzothiazole (0.21 g).

Melting point: 122-124° C. Elemental analysis: as C₂₁H₂₃N₃OS₃Calculated: C, 58.71; H, 5.40; N, 9.78 (%) Found: C, 58.54; H, 5.32; N,9.65 (%)

Example A43 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-benzoxazolylthio)pentane (Compound A37)

In the same manner as in Example A2, 0.1 g of the title compound wasobtained (crystallized from acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and2-mercaptobenzoxazole (0.15 g).

Melting point: 128-130° C. Elemental analysis: as C₁₉H₁₉N₃OS₂Calculated: C, 61.76; H, 5.18; N, 11.38(%) Found: C, 61.49; H, 5.02; N,11.21 (%)

Compound A 38 was also synthesized in a similar manner.

Example A44 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-(5″-phenylbenzoxazolyl)thio)pentane(Compound A39)

In the same manner as in Example A2, 0.2 g of the title compound wasobtained (crystallized from ethyl acetate/acetonitrile) from5-(2′-benzimidazolylthio)pentyl bromide (0.3 g) and2-mercapto-5-phenylbenzoxazole (0.23 g).

Melting point: 100-102° C. Elemental analysis: as C₂₅H₂₃N₃OS₂Calculated: C, 67.38; H, 5.20; N, 9.43 (%) Found: C, 67.45; H, 5.08; N,9.23 (%)

Example B1 Synthesis of1-(2′-benzimidazolylthio)-5-(2″-imidazolylthio)pentane (Compound B1)

5-(2′-Benzimidazolylthio)pentyl bromide (0.30 g) and 2-mercaptoimidazole(0.10 g) were dissolved in ethanol (3 ml), and the resulting solutionwas added with triethylamine (0.16 ml), and then the mixture was heatedunder reflux for 7 hours. After cooling, the reaction mixture wasneutralized with aqueous sodium hydroxide, and the deposited oilyproduct was extracted with ethyl acetate. The extract was washed withwater, and then the solvent was evaporated under reduced pressure. Theresidue was then crystallized from acetonitrile to obtain 0.23 g of thetitle compound.

Melting point: 101-104° C. Elemental analysis: as C₁₅H₁₈N₄S₂ Calculated:C, 56.57; H, 5.70; N, 17.60 (%) Found: C, 56.43; H, 5.61; N, 17.66 (%)

Example B2

In the same manner as in Example B1, compounds mentioned in thefollowing Table 1 were synthesized.

TABLE 1 Melting point Melting point Compound No. (° C.) Compound No.(°C.) Compound B2 57-58 Compound B31 94-95 Compound B4 133-135 CompoundB32 102-103 Compound B5 150-152 Compound B36 145-147 Compound B6 82-83Compound B37 121-123 Compound B7 100-102 Compound B38 108-110 CompoundB8 108-110 Compound B39 149-152 Compound B9 130-133 Compound B40 108-110Compound B10 119-120 Compound B41 79-80 Compound B11 48-49 Compound B4284-85 Compound B12 84-85 Compound B49 102-103 Compound B13 148-149Compound B50 75-77 Compound B14 254-256 Compound B51 88-89 Compound B1589-91 Compound B52 120-123 Compound B16 82-83 Compound B53 125-127Compound B17 182-183 Compound B54 135-137 Compound B18 79-81 CompoundB56 102-104 Compound B19 96-98 Compound B57 106-107 Compound B20 89-91Compound B58 170-172 Compound B22 127-128 Compound B59 174-177 CompoundB24 132-134 Compound B60 166-168 Compound B25 76-77 Compound B61 152-154Compound B26 141-143 Compound B62 130-132 Compound B27 122-124 CompoundB63 125-126 Compound B29 107-109 Compound B66 129-131 Compound B30 98-101

Example B3

In the same manner as in Example B2, Compound B3, Compound B21, CompoundB23, Compound B28, Compound B33, Compound B35, and Compound B55 wereprepared. All of the compounds were obtained as oil. After thecompletion of reactions, reaction mixtures were neutralized with sodiumcarbonate, and extracted with ethyl acetate. The extracts were washedwith water and concentrated, and then resulting residues were purifiedby silica gel column chromatography (developing solvent: ethylacetate/chloroform).

Example B4 Synthesis of 5-(2′-pyridylthio)pentyl bromide hydrobromide

2-Mercaptopyridine (5.55 g) and 1,5-dibromopentane (68.7 g) weredissolved in ethanol (40 ml), and the solution was heated under refluxfor 9 hours. After the solvent was evaporated under reduced pressure,the residue was digested with ethyl acetate (50 ml) and hexane (50 ml)to obtain about 12 g of the title compound as a solid product.

Example B5 Synthesis of1-(2′-(5′-methoxybenzimidazolyl)-5-(2″-pyridylthio)pentane (CompoundB34)

5-(2′-Pyridylthio)pentyl bromide hydrobromide (0.37 g) and5-methoxy-2-mercaptobenzimidazole (0.58 g) were dissolved in ethanol (3ml), and the solution was heated under reflux for 14 hours. Aftercooling, the reaction mixture was neutralized with aqueous sodiumcarbonate, and then extracted with ethyl acetate. The extract was washedwith water, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (developingsolvent: ethyl acetate/chloroform) to obtain 0.3 g of the title compoundas an oil.

Example B6 Synthesis of ethyl 6-(2-pyridylthio)caproate

2-Mercaptopyridine (5.84 g) and 6-bromocaproic acid (9.75 g) weredissolved in ethanol (50 ml), and the solution was heated under refluxfor 14 hours. After cooling, the reaction mixture was added with water,and adjusted to pH 8 with aqueous sodium carbonate. The deposited oilyproduct was extracted with ethyl acetate, and then purified by silicagel column chromatography (developing solvent: chloroform/ethyl acetate)to obtain 13.6 g of the title compound.

Example B7 Synthesis of 1-(2′-benzimidazolylthio)-5-(2″-pyridyl)pentane(Compound B43)

Ethyl 6-(2-pyridylthio)caproate (2.5 g) and o-phenylenediamine (1.1 g)were dissolved in concentrated hydrochloric acid (3.3 ml) and water (7ml), and then the mixture was heated under reflux under nitrogen flowfor 20 hours. After cooling, the reaction mixture was added with water,neutralized with sodium carbonate, and then extracted with ethylacetate. The extract was washed with water and concentrated, and theresidue was crystallized from ethyl acetate/acetonitrile to obtain 1.54g of the title compound.

Melting point: 135-136° C. Elemental analysis: as C₁₆H₁₉N₃S₂ Calculated:C, 67.33; H, 6.71; N, 14.73 (%) Found: C, 67.25; H, 6.62; N, 14.59 (%)

Example B8

In the same manner as in Example B5 and Example B6, compounds listed inTable 2 below were synthesized. Compound B44 (as an oil) was alsosynthesized in a similar manner. For Compound B44, after the completionof the reaction, a reaction mixture was neutralized with sodiumcarbonate, and then extracted with ethyl acetate. The extract was washedwith water and concentrated, and the resulting residue was purified bysilica gel column chromatography (developing solvent:methanol/chloroform).

TABLE 2 Compound No. Melting point (° C.) Compound B45 122-125 CompoundB46 112-114 Compound B47  99-101 Compound B48 88-90

Example B9 Synthesis of5-(2′-(1′-methylbenzimidazolyl)thio)-1-(2″-pyridylthio)pentane (CompoundB64)

5-(2′-Benzimidazolylthio)-1-(2″-pyridylthio)pentane (Compound B30, 0.33g) was dissolved in dimethylformamide (2.2 ml), and the solution wasadded with methyl iodide (0.17 g) and potassium carbonate (0.27 g), andthe the mixture was stirred at 40° C. for three hours. The reactionmixture was poured into water, and then extracted with ethyl acetate.The extract was washed with water, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (developing solvent: ethyl acetate/chloroform) to obtain0.3 g of the title compound as oily product.

Example B10 Synthesis of5-(2′-(1′-propionylbenzimidazolyl)thio)-1-(2″-pyridylthio)pentane(Compound B65)

5-(2′-Benzimidazolylthio)-1-(2″-pyridylthio)pentane (Compound B30, 0.33g) was dissolved in a mixture of dimethylacetamide (1.0 ml),acetonitrile (1.5 ml), and triethylamine (0.3 ml), and then the solutionwas added slowly with propionyl chloride (0.12 ml) at 50° C. Afterstirring was continued for three hours, the reaction mixture was pouredinto water and then extracted with ethyl acetate. The extract was washedwith water, and the solvent was evaporated under reduced pressure. Theresidue was crystallized from water-containing acetonitrile to obtain0.23 g of the title compound.

Melting point: 54-55° C. Elemental analysis: as C₂₀H₂₃N₃OS₂ Calculated:C, 62.30; H, 6.01; N, 10.90 (%) Found: C, 62.18; H, 5.92; N, 10.78 (%)

Example B11 Synthesis of2-(2-(2-p-toluenesulfonyloxy)ethoxy)ethylmercaptobenzimidazole

2-Mercaptobenzimidazole (3.1 g) and diethylene glycol di-p-tosylate (8.3g) were heated under reflux in acetonitrile for 18 hours. After thesolvent was evaporated under reduced pressure, the residue was purifiedby silica gel column chromatography to obtain 2.4 g of the titlecompound (wax-like product).

Example B12 Synthesis of2-(2-(2-(2′-pyridylthio)ethoxy)ethylmercaptobenzimidazole (Compound B67)

In the same manner as in Example A1, 0.21 g of the title compound wasobtained as oily product from2-(2-(2-p-toluenesulfonyloxy)ethoxy)ethylmercaptobenzimidazole (0.27 g)and 2-mercaptopyridine (0.10 g). The oily product was purified by silicagel chromatography (ethyl acetate/chloroform).

Example B13 Synthesis of2-(2-(2-(2-p-toluenesulfonyloxy)ethoxy)ethoxy)ethylmercaptobenzimidazole

2-Mercaptobenzimidazole (3.1 g) and triethylene glycol di-p-tosylate(9.6 g) were heated under reflux in acetonitrile for 18 hours. After thesolvent was evaporated under reduced pressure, 3.3 g of the titlecompound (wax-like product) was separated from the residue by silica gelcolumn chromatography.

Example B14 Synthesis of2-(2-(2-(2-(2′-pyridylthio)ethoxy)ethoxy)ethylmercaptobenzimidazole(Compound B68)

In the same manner as in Example A1, 0.18 g of the title compound wasobtained as oily product from2-(2-(2-(2-p-toluenesulfonyloxy)ethoxy)ethoxy)-ethylmercaptobenzimidazole(0.31 g) and 2-mercaptopyridine (0.10 g). The oily product was purifiedby silica gel chromatography (developing solvent: ethylacetate/chloroform).

Test Example 1

Activity of the compounds of the present invention for suppressing thefoaming of macrophages

Activity of the compounds of the present invention for suppressing thefoaming of macrophages, which triggers arterial sclerosis, was examinedby an in vitro experiment using mouse peritoneal macrophages. 15-Weekold female ICR mice (Nippon SLC) were subjected to bleeding by cuttingoff their cervicalis, and Hanks buffer (Nippon Seiyaku) was injectedinto their peritoneal cavities. After abdominal regions of the mice weremassaged, the buffer was recovered immediately, and then the resultingbuffer was centrifuged at 1,000 r.p.m. for five minutes to collectperitoneal macrophages. Then, the collected macrophages were suspendedin GTI medium (Wako Pure Chemical Industries), and inoculated onto a24-well microtiter plate. After the macrophages were cultivated at 37°C. under 5% CO₂ for two hours, the culture medium was changed withDulbecco Modified Eagle Medium (MEM, Nippon Seiyaku). The macrophageswere further cultivated at 37° C. under 5% CO₂ for 16 hours, and then atest compound and liposomes were added to the culture.

1) Test compound: dissolved in DMSO (Wako Pure Chemical Industries),

2) Liposomes: PC/PSIDCP/CHOL=50150/10/75 (nmol)

PC: Phosphatidylcholine (Funakoshi);

PS: Phosphatidylserine (Funakoshi);

DCP: Dicetylphosphate (Funakoshi);

CHOL: Cholesterol (Sigma)

After cultivation was further continued at 37° C. under 5% CO₂ for 16hours, lipid fraction was extracted with chloroform and methanol. Theextracted lipid fraction was dissolved in isopropyl alcohol, and theproduced cholesterol ester (CE) was quantified by an enzymaticluminescence method. Yield of the cholesterol ester was calculated as arelative ratio based on yield of the control as 100% where no testcompound was added. Cytotoxicity was examined microscopically byobserving morphological alteration of cells. The results are shown inTable 3 and Table 4 set out below. In the tables, compound numberscorrespond to those of the compounds of present invention described inthe examples. The following compound was used as a control for theexperiments using the compounds of B series.

R¹¹ R¹² R² Y m Q H H H S 1

TABLE 3 Rate of CE Compound Dose (μM) synthesis (%) Cytotoxicity A1  541 Not observed A2  5 52 Not observed A3  5 36 Not observed A4  5 41 Notobserved A5  5 39 Not observed A6  5 46 Not observed A7  5 22 Notobserved A8  5 24 Not observed A9  5 28 Not observed A10 5 20 Notobserved A11 5  9 Not observed A12 5 42 Not observed A13 5 58 Notobserved A14 5 42 Not observed A15 5 36 Not observed A16 5 34 Notobserved A17 5 24 Not observed A18 5 52 Not observed A19 5 54 Notobserved A20 5 61 Not observed A21 5 24 Not observed A22 5 20 Notobserved A23 5 34 Not observed A24 5 40 Not observed A25 5 32 Notobserved A26 5 35 Not observed A27 5 48 Not observed A28 5 49 Notobserved A30 5 52 Not observed A31 5 53 Not observed A32 5 62 Notobserved A33 5 13 Not observed A34 5 28 Not observed A35 5 25 Notobserved A36 5 21 Not observed A37 5 13 Not observed A38 5 16 Notobserved A39 5 24 Not observed

TABLE 4 Rate of CE Compound Dose (μM) synthesis (%) Cytotoxicity B1  541 Not observed B2  5 16 Not observed B3  5 34 Not observed B4  5 47 Notobserved B5  5 14 Not observed B6  5 22 Not observed B7  5 21 Notobserved B8  5 24 Not observed B9  5 35 Not observed B10 5 32 Notobserved B11 5 18 Not observed B12 5 14 Not observed B13 5 26 Notobserved B14 5 48 Not observed B15 5 11 Not observed B16 5 9.3 Notobserved B17 5 18 Not observed B18 5 35 Not observed B19 5 21 Notobserved B20 5 24 Not observed B21 5 11 Not observed B22 5 21 Notobserved B23 5 38 Not observed B24 5 9.5 Not observed B25 5 41 Notobserved B26 5 12 Not observed B27 5 15 Not observed B28 5 7.6 Notobserved B29 5 14 Not observed B30 5 9.0 Not observed B31 5 27 Notobserved B32 5 37 Not observed B33 5 18 Not observed B34 5 37 Notobserved B35 5 46 Not observed B36 5 26 Not observed B37 5 20 Notobserved B38 5 22 Not observed B39 5 28 Not observed B40 5 25 Notobserved B41 5 19 Not observed B42 5 12 Not observed B43 5 12 Notobserved B44 5 51 Not observed B45 5 48 Not observed B46 5 36 Notobserved B47 5 23 Not observed B48 5 41 Not observed A49 5 11 Notobserved B50 5 22 Not observed B51 5 24 Not observed B52 5 49 Notobserved B53 5 52 Not observed B54 5 24 Not observed B55 5 52 Notobserved B56 5 18 Not observed B57 5 26 Not observed B58 5 18 Notobserved B59 5 9.2 Not observed B60 5 14 Not observed B61 5 12 Notobserved B62 5 25 Not observed B63 5 15 Not observed B64 5 24 Notobserved B65 5 22 Not observed B66 5 52 Not observed B67 5 54 Notobserved Control Compound 5 102  Not observed

The above results clearly demonstrate that the compounds of the presentinvention remarkably reduced the rate of cholesterol ester synthesiswithout cytotoxicity against macrophages, and that they can suppress thefoaming of macrophages, which directly triggers the onset of arterialsclerosis. In the above tables, a smaller value means a more potentsuppression, and 100% indicates no suppression. On the other hand, thediphenylimidazole derivative used as a control did not exhibit activityfor suppressing the foaming of macrophages.

Test Example 2

Activity of the compounds of the present invention for suppressing theformation of arterial sclerosis lesions (in vivo experiment)

By using rabbits fed with high cholesterol food, effect on lipid inblood and activity of the compounds of the present invention forsuppressing formation of arterial sclerosis lesions were examined.Hypercholesterolemia condition was created by feeding NZW rabbits (male)weighing about 2 kg with high cholesterol feed (100 g/day/rabbit ofOCR-4 [Oriental Yeast]+0.5% cholesterol+0.5% olive oil) for seven days.A group consisting of three rabbits was continuously administered with acompound of the present invention (Compound B16 or Compound B49) forseven days by mixing the compound with the above feed at an amount of100 mg/kg/day/rabbit. Another group consisting of three rabbits was fedsolely with the high cholesterol feed and used as a control group.

Blood was collected from parotid veins with one week interval, and totalcholesterol, LDL cholesterol, HDL cholesterol, GOT, and GPT weremeasured. In the groups administered with the compounds of the presentinvention, LDL cholesterol was reduced by 35% in the group administeredwith Compound B16, and reduced by 30% in the group administered withCompound B49 compared with the control group, although no difference intotal cholesterol was observed. On the other hand, increase of HDLcholesterol by 30% was observed in each of the groups administered withthe compounds of the present invention. No abnormal value was observedfor GOT and GPT during the experiment.

Aortas were removed seven weeks after the administration, andcholesterol deposited on inner vascular walls was quantified. In thegroups administered with Compound B16 or Compound B49, the amount ofdeposited cholesterol was reduced by 40% and 45% compared with control,respectively. These results clearly demonstrate that the compounds ofthe present invention have low toxicity, and have excellent activitiesfor reducing LDL cholesterol, increasing HDL cholesterol, andsuppressing the formation of arterial sclerosis lesions.

INDUSTRIAL APPLICABILITY

The compounds of the present invention are useful as an activeingredient of preventive and/or therapeutic medicament of hyperlipemia,and preventive and/or therapeutic medicament of arterial sclerosis.

What is claimed is:
 1. A benzimidazole compound represented by thefollowing formula:

wherein, Y represents a single bond or sulfur atom; Z represents oxygenatom or sulfur atom; R¹ and R² independently represent hydrogen atom, ahalogen atom, an alkyl group, a haloalkyl group, an aryl group, analkoxy group, an aryloxy group, an alkoxycarbonyl group, analkylsulfamoyl group, an alkylcarbonylamino group, an alkylsulfonylaminogroup, a carbamoyl group, a sulfamoyl group, an acylamino group, asulfonylamino group, cyano group, hydroxyl group, or nitro group; R³represents hydrogen atom, an alkyl group, an acyl group, a sulfonylgroup, an alkoxycarbonyl group, a sulfamoyl group, or a carbamoyl group;n and m each independently represent an integer of 1, 2 or 3, and wheren or m represents 2 or 3, two or three R¹ and R² which may be the sameor different substitute on the benzene ring, respectively; and Lrepresents a linking group selected from a group consisting of a C₂₋₁₂alkylene group, and an alkylene group containing one or more phenylenegroups or ether groups and having 4-12 atoms that constitute a fulllength of a linking chain.
 2. The compound according to claim 1, whereinY represents a single bond or sulfur atom; Z represents oxygen atom orsulfur atom; R¹ and R² independently represent hydrogen atom, a halogenatom, an alkyl group, a haloalkyl group, an aryl group, an alkoxy group,an alkoxycarbonyl group, a sulfamoyl group, an acylamino group, asulfonylamino group, cyano group, hydroxyl group, or nitro group; R³represents hydrogen atom, an alkyl group, or an acyl group; n and mindependently represents 1 or 2; and L represents a linking groupselected from a C₄₋₁₁ alkylene group or an alkylene group containing oneor more ether groups and having 5-8 atoms constituting a full length ofa linking chain.
 3. The compound according to claim 1, wherein Yrepresents a single bond or sulfur atom; Z represents oxygen atom orsulfur atom, R¹ and R² independently represent hydrogen atom, a halogenatom, a C₁₋₄ alkyl group, a halo-C₁₋₄ alkyl group, phenyl group, a C₁₋₄alkoxy group, a C₁₋₄ alkoxycarbonyl group, a C₁₋₄ alkylsulfamoyl group,a C₁₋₄ alkylcarbonylamino group, a C₁₋₄ alkylsulfonylamino group, cyanogroup, hydroxyl group, or nitro group; R³ represents hydrogen atom, aC₁₋₄ alkyl group, or an C₁₋₄ alkylcarbonyl group; n and m independentlyrepresent 1 or 2; and L represents a linking group selected from a C₄₋₁₁alkylene group or an alkylene group containing one or more ether groupsand having 5-8 atoms constituting a full length of a linking chain. 4.The compound according to claim 1, wherein Y represents a single bond orsulfur atom; R¹ represents hydrogen atom, a halogen atom, a C₁₋₄ alkylgroup, or nitro group; n represents 1 or 2; R² represents hydrogen atom,a halogen atom, a C₁₋₄ alkyl group, a halo-C₁₋₄ alkyl group, phenylgroup, a C₁₋₄ alkoxy group, a C₁₋₄ alkoxycarbonyl group, a C₁₋₄alkylsulfamoyl group, a C₁₋₄ alkylcarbonylamino group, a C₁₋₄alkylsulfonylamino group, cyano group, or hydroxyl group; m represents 1or 2; R³ represents hydrogen atom, a C₁₋₄ alkyl group or a C₁₋₄alkylcarbonyl group; Z represents oxygen atom or sulfur atom, and Lrepresents a linking group selected from a C₄₋₁₁ alkylene group and analkylene group containing one or more ether groups and having 5-8 atomsconstituting a full length of a linking chain.
 5. The compound accordingto claim 4, wherein R² is hydrogen atom when Y represents a single bond.6. The compound according to claim 4, wherein Y is sulfur atom when Lrepresents an alkylene group containing one or more ether groups andhaving 5-8 atoms constituting a full length of a linking chain.
 7. Thecompound according to claim 6, wherein R¹ represents a halogen atom; nrepresents 1 or 2; R² represents a halogen atom; and m represents 1 or2.
 8. The compound according to claim 7, wherein m represents
 2. 9. Thecompound according to claim 5, wherein Y is sulfur atom when Lrepresents an alkylene group containing one or more ether groups andhaving 5-8 atoms constituting a full length of a linking chain.
 10. Abenzimidazole compound represented by the following formula:

wherein, Y represents a single bond or sulfur atom; Z represents oxygenatom or sulfur atom; R¹ represents hydrogen atom, a halogen atom, analkyl group, a haloalkyl group, an aryl group, an alkoxy group, anaryloxy group, an alkoxycarbonyl group, an alkylsulfamoyl group, analkylcarbonylamino group, an alkylsulfonylamino group, a carbamoylgroup, a sulfamoyl group, an acylamino group, a sulfonylamino group,cyano group, hydroxyl group, or nitro group; R² represents hydrogenatom, a halogen atom, an alkyl group, a haloalkyl group, an aryl group,an alkoxy group, an aryloxy group, an alkoxycarbonyl group, analkylsulfamoyl group, an alkylcarbonylamino group, an alkylsulfonylaminogroup, a carbamoyl group, a sulfamoyl group, an acylamino group, asulfonylamino group, cyano group, or nitro group; R³ represents hydrogenatom, an alkyl group, an acyl group, a sulfonyl group, an alkoxycarbonylgroup, a sulfamoyl group, or a carbamoyl group; n and m eachindependently represent an integer of 1, 2 or 3, and where n or mrepresents 2 or 3, two or three R¹ and R² which may be the same ordifferent substitute on the benzene ring, respectively; and L representsa linking group selected from a group consisting of a C₂₋₁₂ alkylenegroup, and an alkylene group containing one or more phenylene groups orether groups and having 4-12 atoms that constitute a full length of alinking chain.
 11. A pharmaceutical composition comprising the compoundaccording to claim 1 as an active ingredient together with apharmaceutically acceptable additive.
 12. A method for preventive ortherapeutic treatment of a disease selected from the group consisting ofhyperlipemia and arterial sclerosis, which comprises the step ofadministering to a patient a preventively and therapeutically effectiveamount of the compound according to claim
 1. 13. A method for preventiveor therapeutic treatment of hyperlipemia, which comprises administeringto a patient a preventive or therapeutically effective amount of thecomposition of claim
 1. 14. A method for preventive or therapeutictreatment of arterial sclerosis, which comprises administering to apatient a preventive or therapeutically effective amount of thecomposition of claim
 1. 15. A method for preventive or therapeutictreatment of increased levels of cholesterol which comprises the step ofadministering to a patient a preventive or therapeutically effectiveamount of the composition of claim 1 for lowering cholesterol in saidpatient.
 16. A method for suppressing foaming of macrophages whichcomprises administering to a patient an effective amount of thecomposition of claim 1 for suppressing foaming of macrophages.
 17. Amethod for retracting arterial sclerosis lesions which comprisesadministering to a patient an effective amount of the composition ofclaim 1 for retracting arterial sclerosis lesions.
 18. A method forinhibiting formation of arterial sclerosis lesions which comprisesadministering to a patient an effective amount of the composition ofclaim 1 for inhibiting formation of arterial sclerosis lesions.